Target Information

Target General Information

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Target ID

T11451 (Former ID: TTDC00107)

Target Name

Toll-like receptor 9 (TLR9)

Synonyms

UNQ5798/PRO19605; TLR-9; CD289

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Gene Name

TLR9

Target Type

Clinical trial target

[1]

Disease

[+] 4 Target-related Diseases

Colorectal cancer [ICD-11: 2B91]

Hepatitis virus infection [ICD-11: 1E50-1E51]

Melanoma [ICD-11: 2C30]

Prostate cancer [ICD-11: 2C82]

Function

Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Controls lymphocyte response to Helicobacter infection. Upon CpG stimulation, induces B-cell proliferation, activation, survival and antibody production.

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BioChemical Class

Toll-like receptor

UniProt ID

TLR9_HUMAN

Sequence

MGFCRSALHPLSLLVQAIMLAMTLALGTLPAFLPCELQPHGLVNCNWLFLKSVPHFSMAA
PRGNVTSLSLSSNRIHHLHDSDFAHLPSLRHLNLKWNCPPVGLSPMHFPCHMTIEPSTFL
AVPTLEELNLSYNNIMTVPALPKSLISLSLSHTNILMLDSASLAGLHALRFLFMDGNCYY
KNPCRQALEVAPGALLGLGNLTHLSLKYNNLTVVPRNLPSSLEYLLLSYNRIVKLAPEDL
ANLTALRVLDVGGNCRRCDHAPNPCMECPRHFPQLHPDTFSHLSRLEGLVLKDSSLSWLN
ASWFRGLGNLRVLDLSENFLYKCITKTKAFQGLTQLRKLNLSFNYQKRVSFAHLSLAPSF
GSLVALKELDMHGIFFRSLDETTLRPLARLPMLQTLRLQMNFINQAQLGIFRAFPGLRYV
DLSDNRISGASELTATMGEADGGEKVWLQPGDLAPAPVDTPSSEDFRPNCSTLNFTLDLS
RNNLVTVQPEMFAQLSHLQCLRLSHNCISQAVNGSQFLPLTGLQVLDLSHNKLDLYHEHS
FTELPRLEALDLSYNSQPFGMQGVGHNFSFVAHLRTLRHLSLAHNNIHSQVSQQLCSTSL
RALDFSGNALGHMWAEGDLYLHFFQGLSGLIWLDLSQNRLHTLLPQTLRNLPKSLQVLRL
RDNYLAFFKWWSLHFLPKLEVLDLAGNQLKALTNGSLPAGTRLRRLDVSCNSISFVAPGF
FSKAKELRELNLSANALKTVDHSWFGPLASALQILDVSANPLHCACGAAFMDFLLEVQAA
VPGLPSRVKCGSPGQLQGLSIFAQDLRLCLDEALSWDCFALSLLAVALGLGVPMLHHLCG
WDLWYCFHLCLAWLPWRGRQSGRDEDALPYDAFVVFDKTQSAVADWVYNELRGQLEECRG
RWALRLCLEERDWLPGKTLFENLWASVYGSRKTLFVLAHTDRVSGLLRASFLLAQQRLLE
DRKDVVVLVILSPDGRRSRYVRLRQRLCRQSVLLWPHQPSGQRSFWAQLGMALTRDNHHF
YNRNFCQGPTAE

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

HIT2.0 ID

T73ATB

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 27 Clinical Trial Drugs

Cadi-05

Drug Info

Phase 3

Prostate cancer

[2]

IMO-2125

Drug Info

Phase 3

Melanoma

[3], [4]

MGN-1703

Drug Info

Phase 3

Colorectal cancer

[5]

SD-101

Drug Info

Phase 3

Hepatitis C virus infection

[6]

Tilsotolimod

Drug Info

Phase 3

Melanoma

[7]

BL-7040

Drug Info

Phase 2

Inflammatory bowel disease

[8]

CpG-10101

Drug Info

Phase 2

Hepatitis C virus infection

[9]

CYT003

Drug Info

Phase 2

Asthma

[10]

IMO-2055

Drug Info

Phase 2

Solid tumour/cancer

[11]

IMO-3100

Drug Info

Phase 2

Psoriasis vulgaris

[12]

JVRS-100

Drug Info

Phase 2

leukaemia

[13]

Lefitolimod

Drug Info

Phase 2

Human immunodeficiency virus-1 infection

[14]

MIS-416

Drug Info

Phase 2

Autoimmune diabetes

[15]

Tolamba

Drug Info

Phase 2

Allergic rhinitis

[16]

Zadaxin/lamivudine

Drug Info

Phase 2

Hepatitis B virus infection

[17]

AST-008

Drug Info

Phase 1

Solid tumour/cancer

[3]

AZD1419

Drug Info

Phase 1

Asthma

[18]

Cavrotolimod

Drug Info

Phase 1

Solid tumour/cancer

[19]

CMP-001

Drug Info

Phase 1

Melanoma

[3], [4], [20], [21]

CPG 52364

Drug Info

Phase 1

Systemic lupus erythematosus

[22]

DV-1179

Drug Info

Phase 1

Autoimmune disease

[23]

DV281

Drug Info

Phase 1

Non-small-cell lung cancer

[3]

GNKG-168

Drug Info

Phase 1

Chronic lymphocytic leukaemia

[24]

Litenimod

Drug Info

Phase 1

Glioblastoma multiforme

[25]

MGN-1706

Drug Info

Phase 1

Solid tumour/cancer

[26]

N-8295

Drug Info

Phase 1

Influenza virus infection

[27]

SAR-21609

Drug Info

Phase 1

Asthma

[28]

Discontinued Drug(s)

[+] 4 Discontinued Drugs

IR-103

Drug Info

Discontinued in Phase 3

Human immunodeficiency virus infection

[29]

Agatolimod

Drug Info

Discontinued in Phase 2

Lung cancer

[30]

IM0-8400

Drug Info

Discontinued in Phase 1/2

Diffuse large B-cell lymphoma

[31]

AVE0675

Drug Info

Terminated

Asthma

[32]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

IMO-2134

Drug Info

Preclinical

Allergy

[11]

Mode of Action

[+] 4 Modes of Action

Agonist

[+] 18 Agonist drugs

IMO-2125

Drug Info

[11]

MGN-1703

Drug Info

[34]

Tilsotolimod

Drug Info

[35]

CpG-10101

Drug Info

[37]

CYT003

Drug Info

[10]

IMO-2055

Drug Info

[11]

Lefitolimod

Drug Info

[40]

AST-008

Drug Info

[3]

AZD1419

Drug Info

[44]

Cavrotolimod

Drug Info

[45]

CMP-001

Drug Info

[46]

DV281

Drug Info

[3]

MGN-1706

Drug Info

[50]

SAR-21609

Drug Info

[33]

Agatolimod

Drug Info

[52], [53]

IMO-2134

Drug Info

[11]

AVE0675

Drug Info

[55]

COV08-0064

Drug Info

[56]

Activator

[+] 1 Activator drugs

BL-7040

Drug Info

[36]

Modulator

[+] 7 Modulator drugs

IMO-3100

Drug Info

[38]

MIS-416

Drug Info

[41]

Zadaxin/lamivudine

Drug Info

[43]

DV-1179

Drug Info

[48]

GNKG-168

Drug Info

[49]

Litenimod

Drug Info

[50]

DIMS-9054

Drug Info

[50]

Antagonist

[+] 3 Antagonist drugs

CPG 52364

Drug Info

[47]

IM0-8400

Drug Info

[54]

ODN-2088

Drug Info

[57]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Leucine-rich repeat and fibronectin type-III domain-containing protein 5 (LRFN5)	PF07679 ; PF13306	35.135 (39/111)	9.22E-06
Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1)	PF12796 ; PF16095 ; PF00069 ; PF08477 More >>	27.465 (78/284)	4.61E-05
Leucine-rich repeat and guanylate kinase domain-containing protein (LRGUK)	PF00625 ; PF14580	32.298 (52/161)	2.19E-04
Imidazoline receptor 1 (IR1)	PF00787	31.148 (38/122)	8.04E-04
Serine/threonine-protein kinase 11-interacting protein (STK11IP)	PF15904	36.283 (41/113)	4.00E-03

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Toll-like receptor signaling pathway	hsa04620	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	3	Degree centrality	3.22E-04	Betweenness centrality	1.94E-05
Closeness centrality	2.03E-01	Radiality	1.35E+01	Clustering coefficient	3.33E-01
Neighborhood connectivity	2.40E+01	Topological coefficient	3.94E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 7 KEGG Pathways

Toll-like receptor signaling pathway

Chagas disease (American trypanosomiasis)

African trypanosomiasis

Malaria

Tuberculosis

Measles

Herpes simplex infection

NetPath Pathway

[+] 1 NetPath Pathways

BCR Signaling Pathway

Panther Pathway

[+] 1 Panther Pathways

Toll receptor signaling pathway

Reactome

[+] 5 Reactome Pathways

PI3K Cascade

Trafficking and processing of endosomal TLR

TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling

TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation

MyD88 dependent cascade initiated on endosome

WikiPathways

[+] 6 WikiPathways

Toll-like receptor signaling pathway

Toll-Like Receptors Cascades

MyD88 dependent cascade initiated on endosome

Trafficking and processing of endosomal TLR

Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)

Regulation of toll-like receptor signaling pathway

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Novel drugs targeting Toll-like receptors for antiviral therapy. Future Virol. 2014 September; 9(9): 811-829.

REF 2

ClinicalTrials.gov (NCT00810849) A Trial of Adjunctive Prednisolone and Mycobacterium w Immunotherapy in Tuberculous Pericarditis. U.S. National Institutes of Health.

REF 3

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 4

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 5

ClinicalTrials.gov (NCT02077868) Evaluation of MGN1703 Maintenance Treatment in Patients With mCRC With Tumor Reduction During Induction Treatment. U.S. National Institutes of Health.

REF 6

ClinicalTrials.gov (NCT02384460) Study of Efficacy and Safety of SD-101 Cream in Patients With Epidermolysis Bullosa. U.S. National Institutes of Health.

REF 7

ClinicalTrials.gov (NCT03445533) A Study of IMO-2125 in Combination With Ipilimumab Versus Ipilimumab Alone in Subjects With Anti-PD-1 Refractory Melanoma (ILLUMINATE-301) (ILLUMINATE-301). U.S. National Institutes of Health.

REF 8

ClinicalTrials.gov (NCT01506362) Efficacy, Pharmacodynamics, Safety and Tolerability of Oral BL-7040 in Patients With Moderately Active Ulcerative Colitis. U.S. National Institutes of Health.

REF 9

ClinicalTrials.gov (NCT00277238) CPG10101 Combination Therapy For The Treatment Of Hepatitis C In Non-Responder (Null And Partial Responder) Hepatitis C Virus (HCV) Genotype 1 Infected Subjects. U.S.National Institutes of Health.

REF 10

CYT003, a TLR9 agonist, in persistent allergic asthma - a randomized placebo-controlled Phase 2b study. Allergy. 2015 Sep;70(9):1160-8.

REF 11

Clinical pipeline report, company report or official report of Idera Pharmaceuticals (2011).

REF 12

ClinicalTrials.gov (NCT01622348) Trial of IMO-3100 in Patients With Moderate to Severe Plaque Psoriasis. U.S. National Institutes of Health.

REF 13

ClinicalTrials.gov (NCT00936468) Safety, Tolerability and Immunogenicity of Fluzone With and Without JVRS-100 in Elderly Subjects. U.S. National Institutes of Health.

REF 14

ClinicalTrials.gov (NCT03837756) Combining TLR9 Agonist With bNAbs for Reservoir Reduction and Immunological Control of HIV (TITAN). U.S. National Institutes of Health.

REF 15

Targeting Innate Receptors with MIS416 Reshapes Th Responses and Suppresses CNS Disease in a Mouse Model of Multiple Sclerosis. PLoS ONE 9(1): e87712. January 31, 2014.

REF 16

ClinicalTrials.gov (NCT00537355) An Evaluation of the Efficacy and Safety of TOLAMBA for Ragweed-Allergic Rhinitis in an Environmental Exposure Chamber. U.S. National Institutes of Health.

REF 17

Clinical pipeline report, company report or official report of SciClone.

REF 18

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025034)

REF 19

ClinicalTrials.gov (NCT03684785) Intratumoral Cavrotolimod Combined With Pembrolizumab or Cemiplimab in Patients With Merkel Cell Carcinoma, Cutaneous Squamous Cell Carcinoma, or Other Advanced Solid Tumors. U.S. National Institutes of Health.

REF 20

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 21

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 22

Treatment of systemic lupus erythematosus: new therapeutic avenues and blind alleys. Nat Rev Rheumatol. 2014 Jan;10(1):23-34.

REF 23

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 24

ClinicalTrials.gov (NCT01743807) Phase I Study of GNKG168 in Acute Lymphoblastic Leukemia and Acute Myelogenous Leukemia. U.S. National Institutes of Health.

REF 25

Clinical pipeline report, company report or official report of Oligovax SAS.

REF 26

Targeting Toll-like receptors: emerging therapeutics Nat Rev Drug Discov. 2010 Apr;9(4):293-307.

REF 27

Clinical pipeline report, company report or official report of Dynavax Technologies Corp.

REF 28

Targeting Toll-like receptors: emerging therapeutics. Nat Rev Drug Discov. 2010 Apr;9(4):293-307.

REF 29

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019204)

REF 30

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011959)

REF 31

Clinical pipeline report, company report or official report of Idera Pharmaceuticals.

REF 32

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027402)

REF 33

Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. Oncoimmunology. 2012 August 1; 1(5): 699-716.

REF 34

Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist, in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised, double-blind, placebo-controlled trial. J Cancer Res Clin Oncol. 2014 Sep;140(9):1615-24.

REF 35

Tilsotolimod with ipilimumab drives tumor responses in anti-PD-1 refractory melanoma. Cancer Discov. 2021 Mar 11;candisc.1546.2020.

REF 36

Gut feeling: MicroRNA discriminators of the intestinal TLR9-cholinergic links. Int Immunopharmacol. 2015 Nov;29(1):8-14.

REF 37

Safety, pharmacokinetics and immune effects in normal volunteers of CPG 10101 (ACTILON), an investigational synthetic toll-like receptor 9 agonist. Antivir Ther. 2007;12(5):741-51.

REF 38

Company report (Iderapharma)

REF 39

Cationic lipid/DNA complexes (JVRS-100) combined with influenza vaccine (Fluzone ) increases antibody response, cellular immunity, and antigenically drifted protection. Vaccine. 2009 June 12; 27(29):3811-3820.

REF 40

Beneficial modulation of the tumor microenvironment and generation of anti-tumor responses by TLR9 agonist lefitolimod alone and in combination with checkpoint inhibitors. Oncoimmunology. 2019 Sep 20;8(12):e1659096.

REF 41

DOI: 10.1371/journal.pone.0087712

REF 42

Phase II study of a TLR-9 agonist (1018 ISS) with rituximab in patients with relapsed or refractory follicular lymphoma. Br J Haematol. 2009 August; 146(3): 282-291.

REF 43

Zadaxin (thymosin alpha1) for the treatment of viral hepatitis. Expert Opin Investig Drugs. 1999 Mar;8(3):281-7.

REF 44

Clinical pipeline report, company report or official report of dynavax.

REF 45

Clinical pipeline report, company report or official report of Exicure.

REF 46

Clinical pipeline report, company report or official report of Checkmate Pharmaceuticals.

REF 47

Coley Pharmaceutical Group Diversifies Pipeline with First-in-Class TLR Antagonist for the Treatment of Systemic Lupus Erythematosus. Lupus Foundation of America, Inc. 2007.

REF 48

Company report (Dynavax)

REF 49

National Cancer Institute Drug Dictionary (drug id 662816).

REF 50

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1759).

REF 51

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019871)

REF 52

Pfizer. Product Development Pipeline. March 31 2009.

REF 53

CPG-7909 (PF-3512676, ProMune): toll-like receptor-9 agonist in cancer therapy. Expert Opin Biol Ther. 2007 Aug;7(8):1257-66.

REF 54

Clinical pipeline report, company report or official report of Idera Pharmaceuticals.

REF 55

Pharma & Vaccines. Product Development Pipeline. April 29 2009.

REF 56

The novel TLR9 antagonist COV08-0064 protects from ischemia/reperfusion injury in non-steatotic and steatotic mice livers. Biochem Pharmacol. 2016 Jul 15;112:90-101.

REF 57

Toll-like receptor 9 antagonism modulates astrocyte function and preserves proximal axons following spinal cord injury. Brain Behav Immun. 2019 Aug;80:328-343.

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